Monoamine oxidase (MAO) is an important enzyme in the catabolism of the neurotransmitters NE, DA and 5-HT. It has been linked to various psychiatric diseases and MAO inhibitors are clinically effective in the treatment of Parkinson's disease and depression. However, the use of these drugs is hampered by their lack of specificity and diverse toxic side effects. Our goal is to learn more about the cellular properties of MAO. This knowledge can then be applied towards a more effective and rational treatment of these psychiatric disorders. We have recently isolated a polypeptide from plasma, CSF and brain tissues that inhibited MAO-A activity in vitro. Our objective is to further access the physiological activity of this endogenous modulator by (i) determining its ability to inhibit 5-HT metabolism in synaptosomes in vitro and in brain regions after intracerebral injections, and (ii) determining its ability to mimic the effects of synthetic MAO inhibitors in potentiating the tryptophan and 5-HTP induced hyperactivity syndrome. The metabolism of 5-HT will be measured by (a) changes in the steady state levels of 5-HT and 5-HIAA, and (b) changes in the level of newly synthesized 3H-5-HIAA from 3H-5-HT, using the HPLC with electrochemical detection. The hyperactivity syndrome will be monitored automatically with the activity cage and manually by a 'blind' rater. The results of these experiments will be compared to that of the synthetic MAO inhibitors. A parallel response between the two will indicate that the endogenous modulator is capable of affecting 5-HT neuronal functions, leading to physiological changes in behavior.